Fulvestrant (7-alpha-[9-(4,4,5,5,5-penta fluoropentylsulphinyl)nonyl]estra-1,3,5-(10)-triene-3,17-beta-diol), has the structural formula (I):
and is commercially available as an oily parenteral formulation for monthly intramuscular administration under the tradename FASLODEX® (AstraZeneca Pharmaceuticals LP). Fulvestrant contains 6 asymmetric carbon atoms and a stereogenic sulphoxide in the side chain. The active ingredient of FASLODEX® is a mixture of 2 diastereoisomers: fulvestrant sulphoxide A and B, having the same absolute configuration at each of the stereogenic centers in the steroid system but different absolute configurations at the sulphur atom. Commercially available Fulvestrant is a mixture of two diastereoisomers, Fulvestrant Sulphoxide A and Fulvestrant Sulphoxide B. Fulvestrant formulations have been described in, for example, U.S. Pat. Nos. 6,774,122 and 7,456,160.
Fulvestrant acts as an estrogen receptor antagonist without agonist properties, blocking the trophic actions of estrogens without itself having any partial agonist (estrogen-like) activity on the endometrium. Fulvestrant binds to estrogen receptors (ERs) in a competitive manner with affinity comparable with that of estradiol and downregulates the ER protein in human breast cancer cells. Data from pre-clinical studies indicated that fulvestrant is effective against human breast cancer cells and xenografts displaying acquired resistance to tamoxifen or letrozole. See, Osborne et al, Cancer Chemother. Pharmacol., 134(2): 89-95 (1994); Osborne et al, Journal of the National Cancer Institute, 87(10) 746-750 (1995); and Long and Jelovac, Clinical Cancer Research, 8:2378-2388 (2002). FASLODEX® is currently indicated for use in the treatment of hormone receptor positive metastatic breast cancer in postmenopausal women with disease progression following antiestrogen therapy. Bross et al., The Oncologist, 7:477-480 (2002).
Fulvestrant's characteristics, such as having a very high lipophilicity, extremely low aqueous solubility and the fact that it is only ionized at very high pH, present formulation challenges and account for its administration as an oily intramuscular injection. Commercially available FASLODEX® is an intramuscular injection of 250 mg fulvestrant in a sterile oily solution in either a single 5 ml pro-filled syringe or two 2.5 ml pre-filled syringes, as long acting injection(s). The long acting FASLODEX® intramuscular depot formulation contains benzyl alcohol and castor oil as solvents and is designed to deliver the dose of 250 mg of fulvestrant over a 1 month period from a single 5 ml intramuscular injection in the buttock or two 2.5 ml intramuscular injection into the buttocks. Bross et al., The Oncologist, 7:477-480 (2002). While this required monthly dose of 250 mg or bi-monthly dose of 125 mg of fulvestrant is effective, it takes approximately 3-6 months to achieve steady-state plasma levels of fulvestrant. See, e.g., Chia and Gradishar, The Breast, 17:S16-S21 (2008); and William et al., Clinical Breast Cancer, 6(1):S23-S29 (2005). Decreasing the time in which steady-state plasma levels are reached following administration of fulvestrant may reduce the time taken to achieve a therapeutic response, which can be particularly beneficial for patients who would otherwise experience disease progression early during endocrine treatment. Robertson, J. F. R, The Oncologist, 12:744-784 (2007). In addition, increasing ER downregulation with higher doses of fulvestrant may provide a better treatment response. Id.
Alternative dosing regimens of FASLODEX® have been suggested as a way to enhance the efficacy of fulvestrant therapy. However, even if alternative dosing regimens of FASLODEX® were to provide a therapeutic benefit, administration of fulvestrant as an intramuscular injection still has various disadvantages. For example, injection-site reaction, including transient pain and inflammation, is one of the most common drug-related events reported for FASLODEX®. Bross, The Oncologist, 7:477-480 (2002). Other disadvantages associated with intramuscular administration include nerve/bone damage during needle insertion, pain and tissue damage, accidental injection of air into artery or vein, extreme pain and/or tissue damage. Such events would only increase if new dosing regimens require more frequent injections. Intramuscular injections may also be inconvenient to the patient and be a source of anxiety, which can adversely impact patient compliance. In one study of patient preference for administration of endocrine therapy by injection or oral tablets, the majority of respondants generally preferred administration via daily tablets. L. Fallowfield, et ah, Annals of Oncology, 17: 205-210 (2006). Given the importance of patient compliance to therapeutic outcome, patient preference is an important consideration. In addition, intramuscular injections are not suitable for all patients. For example, patients with certain blood disorders {e.g., bleeding diatheses, thrombocytopenia) or receiving anticoagulants may not be suitable candidates for administration of fulvestrant by intramuscular injection.
Delivery of fulvestrant via non-invasive formulations, such as oral delivery, have been explored, but adequate bioavailability, aqueous solubility, and target formulation concentration could not be achieved, presumably due to the high lipophilicity and low aqueous solubility of fiulvestrant. See, e.g., Harrison M., et al., (2003) Proc. ASCO, 22: 45, abstract 311.
There therefore remains a need for additional fulvestrant formulations, such as formulations that render fulvestrant suitable for oral, intranasal and/or sublingual administration.